Altered Brain Serotonin Homeostasis and Locomotor Insensitivity to 3,4-Methylenedioxymethamphetamine (“Ecstasy”) in Serotonin Transporter-Deficient Mice
- Dietmar Bengel1,
- Dennis L. Murphy1,
- Anne M. Andrews1,
- Christine H. Wichems1,
- Douglas Feltner2,
- Armin Heils3,
- Rainald Mössner3,
- Heiner Westphal2 and
- Klaus-Peter Lesch3
- 1Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892-1264 (D.B., D.L.M., A.M.A., C.H.W.),2Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20982 (D.F., H.W.), 3Department of Psychiatry, University of Würzburg, 97080 Würzburg, Germany (A.H., R.M., K.-P.L.)
Abstract
The sodium-dependent, high affinity serotonin [5-hydroxytryptamine (5-HT)] transporter (5-HTT) provides the primary mechanism for inactivation of 5-HT after its release into the synaptic cleft. To further evaluate the function of the 5-HTT, the murine gene was disrupted by homologous recombination. Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT−/− mice. High affinity [3H]5-HT uptake was completely absent in 5-HTT−/− mice, confirming a physiologically effective knockout of the 5-HTT gene. 5-HTT binding sites labeled with [125I]3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester were reduced in a gene dose-dependent manner, with no demonstrable binding in 5-HTT−/− mutants. In adult 5-HTT−/− mice, marked reductions (60–80%) in 5-HT concentrations were measured in several brain regions. While (+)-amphetamine-induced hyperactivity did not differ across genotypes, the locomotor enhancing effects of (+)-3,4-methylenedioxymethamphetamine, a substituted amphetamine that releases 5-HT via a transporter-dependent mechanism, was completely absent in 5-HTT−/− mutants. Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity.
Footnotes
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Send reprint requests to: Klaus-Peter Lesch, M.D., Department of Psychiatry, University of Würzburg, Füchsleinstr. 15, 97080 Würzburg, Germany. E-mail:kplesch{at}mail.uni-wuerzburg.de
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This work was supported by the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, the European Commission, and the Intramural Research Program of the National Institute of Mental Health. Additional assistance came from a Howard Hughes Medical Institute Fellowship for physicians (D.F.) and from support by the Hermann and Lilly Schilling Foundation (K.-P.L.).
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine (serotonin)
- 5-HTT
- 5-hydroxytryptamine transporter
- MDMA
- 3,4-methylenedioxymethamphetamine
- ES
- embryonic stem
- kb
- kilobase pair
- RTI-55
- 3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester
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- Received August 1, 1997.
- Accepted December 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
